Tunable hybrid iii-v/ iv laser sensor system-on-a-chip for real-time monitoring of a blood constituent concentration level

ABSTRACT

A spectroscopic laser sensor based on hybrid III-V/IV system-on-a-chip technology. The laser sensor is configured to either (i) be used with a fiber-optic probe connected to an intravenous/intra-arterial optical catheter for direct invasive blood analyte concentration level measurement or (ii) be used to measure blood analyte concentration level non-invasively through an optical interface attached, e.g., to the skin or fingernail bed of a human. The sensor includes a III-V gain-chip, e.g., an AlGaInAsSb/GaSb based gain-chip and a photonic integrated circuit, with laser wavelength filtering, laser wavelength tuning, laser wavelength monitoring, laser signal monitoring and signal output sections realized on a chip by combining IV-based semiconductor substrates and flip-chip AlGaInAsSb/GaSb based photodetectors and embedded electronics for signal processing. Embodiments of the invention may be applied for real-time monitoring of critical blood analyte concentration levels such as lactates, urea, glucose, ammonia, albumin, etc.

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalApplication Ser. No. 62/509,301 filed May 22, 2017, U.S. ProvisionalApplication Ser. No. 62/539,759 filed Aug. 1, 2017, and U.S. ProvisionalApplication Ser. No. 62/595,283 filed Dec. 6, 2017, each of which isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

Embodiments of the invention relate generally to semiconductor-basedspectroscopic sensors based on hybrid III-V/IV system-on-a-chiptechnology for real-time continuous monitoring of blood analyteconcentration levels in a human body, such as blood lactate and bloodglucose concentration level monitoring.

BACKGROUND

According to American Association for Clinical Chemistry (AACC), bloodanalytes such as glucose, lactate, urea, creatinine, ammonia, albuminand others are considered as most important blood analytes in criticalcare medicine which are required to be monitored in order to diagnoseand treat such critical cases as sepsis, organ dysfunction and failure,hypoxia, diabetes, dehydration, and others.

In some case, such as sepsis, which has high mortality rate in excess of30%, time is a critical factor and real-time monitoring of importantblood analytes such as lactate is of paramount importance and candirectly affect the survivability of the patient. It is reported that incase of sepsis, mortality increases by 8% with every hour of treatmentdelay; therefore, timely diagnosis is of paramount importance. Only inUSA, sepsis alone is responsible for over 250 000 cases that result indeath, which is the third most common cause of death in US. Moreover,sepsis was the most expensive in-patient cost in American hospitals in2014, at nearly 24 billion USD each year. See www.sepsis.com/definitionand http://www.sepsis.org/faq/, accessed Mar. 10, 2017 and incorporatedherein by reference in its entirety. Timely diagnosed sepsis combinedwith proper treatment is a critical factor that could save patients'lives. Lactate is a prognostic marker in case of sepsis and real-timemonitoring of blood lactate level is critical for early warning as wellas treatment effectiveness.

Earlier works have reported on various monitoring techniques includingthose that utilize light. See U.S. Patent Publication Nos. 2014/0176958and 2012/0226118, and U.S. Pat. Nos. 6,442,413 and 5,945,676,incorporated herein by reference in their entireties. These reportedsystems, however, are either implantable, use moving parts such as MEMSmirrors, and/or use broadband sources not related to III-V/IVtechnology. Implantable sensors often carry additional risks related tobiocompatibility and risk of additional infection as well as they havelimitations in terms of implanting location for direct monitoring whichcan be a limiting factor in some applications. Broadband sources sufferfrom poor spectral power density and require complex wavelengthdiscrimination schemes such as waveguide arrays and photodetector arrays(2×12 or similar as in U.S. Patent Publication No. 2012/0226118.)

SUMMARY

A sensor in accordance with embodiments of the invention can enter anexisting intravascular, i.e., an intravenous or intra-arterial catheterthat has an optical fiber interface, thus allowing the sensor to be usedfor direct blood metabolite level measurement in real-time. This isespecially useful in critical care, such as intensive care units andoperating theaters where blood metabolite concentration level accuracyis critical and especially in particular cases such as sepsis, whereblood metabolite level can differ within the body.

Embodiments of the configurations described herein provide a significantadvantage. For example, existing methods of lactate level measurementtypically are implemented at point of care or at remote lab testing.This results in test turn-around time ranging from a few minutes to afew hours. In particular, point-of-care testing typically requires a fewminutes turn-around time for a test that is non-real time—i.e., theblood has to be drawn from the patient and processed by an instrumentproviding a single data point. Real-time measurements, in accordancewith embodiments of the invention, allow for continuous collection ofmultiple data points over a period of time providing importantinformation of the historic trend that can be vital in evaluatingeffectiveness of treatment.

For applications where accuracy is less critical and where bloodmetabolite level differences within the body is of less significancesuch as in case of athletics and professional sports, a non-invasivesolution sending light through tissue from outside can be used. Thelatter solution may be used by medical clinics for patients outsideintensive care units (ICUs) and operating theaters as early warningsystems together with other existing measurements, such as oximetry,without excess burden on the patient. Moreover, improving early warningprevention of such complicated cases like sepsis is expected to savesignificant costs in terms of treatment and hospital stay.

Embodiments of the invention include sensors based on a widely tunablelaser concept realized in III-V/IV technology, III-V refers tosemiconductor materials based on AlGInNAsSbP and different combinationthereof, typically known as III-V semiconductors to those skilled in theart. IV refers to group IV-based semiconductor substrates and theirtechnology platforms such as silicon, silicon-on-insulator (SOI),germanium-on-insulator (GOI), germanium on silicon, silicon nitride onsilicon, silicon nitride-on-insulator, and siliconnitride-on-silicon-on-insulator. The group IV technology uses processesthat are standard industrial CMOS fabrication steps used in themicroelectronics industry and allow realization of photonic integratedcircuits based on group IV materials and their derivatives. Thenon-implantable sensors do not have any moving mechanical parts, andoffer direct blood metabolite concentration level measurement inreal-time by means of laser absorption spectroscopy. An exemplary widelytunable laser may be manufactured by a hybrid combination of GaSb basedgain-chip active medium and external filter realized in a silicon, asilicon nitride, silicon-on-insulator, siliconnitride-on-silicon-on-insulator, silicon nitride on insulator or agermanium-on-insulator platform chip. See e.g., R. Wang et al., OpticsExpress, 24 (25), 28977-28986 (2016), the disclosure of which isspecifically intended to be incorporated herein as part of thisdisclosure in its entirety to illustrate the fabrication and use ofwidely tunable lasers. This laser is combined with simple wavelengthcontrol circuitry and a few GaSb-based photodiodes for signal detectionto provide high signal brightness and, thereby, sensitivity.

In an aspect, embodiments of the invention relate to a laser-basedsensor system-on-a-chip for real-time monitoring of a blood constituentconcentration level in a subject. The system-on-a-chip includes (i) atunable hybrid III-V/IV laser sensor; and (ii) a fiber-optic interfacecoupled to the laser sensor, the interface including a probe. Duringuse, the laser sensor is remote from the subject and the probe is inoptical communication with the subject.

One or more of the following features may be included. IV includesgroup-IV based semiconductor substrate such as silicon,silicon-on-insulator, silicon nitride on silicon-on-insulator,germanium-on-insulator, and silicon nitride on silicon. The tunablelaser sensor may include a III-V gain-chip and a photonic integratedcircuit disposed on a group IV semiconductor such assilicon-on-insulator, silicon nitride, silicon nitride on silicon oninsulator, germanium-silicon or germanium-on-insulator substrate, thephotonic integrated circuit (i) being configured to perform wavelengthfiltering and tuning functions based on Vernier effect and (ii) definingan external cavity for the III-V gain-chip.

The photonic integrated circuit may include a spot-size mode converter,a phase control section, and a first resonator having a firstfree-spectral range coupled to a second resonator having a secondfree-spectral range. The first and second resonators may be, e.g., microring resonators, sampled Bragg reflectors, or distributed feedbackreflectors. The first free-spectral range may be different from thesecond free-spectral range.

The coupled first and second resonators, the III-V gain-chip, spot-sizemode converter, and phase control section may cooperate to enableVernier effect-based tuning of the tunable laser sensor. The tunablelaser sensor may be configured such that, in operation, applying atleast one of current or heat to at least one of the coupled resonatorsto change an effective refractive index thereof effects a change in awavelength of a laser generated by the gain-chip.

The III-V gain-chip may be edge-coupled to the photonic integratedcircuit, e.g., by a grating coupler.

The laser sensor may include at least one III-V photodiode coupled to aphotonic integrated circuit by at least one of flip-chip bonding,gluing, transfer printing technology, or side coupling.

A discrete III-V photodiode may be disposed remotely from the tunablelaser sensor, wherein, in use, a reflected signal from the subject iscollected by the discrete III-V photodiode. The photonic integratedcircuit may include a signal and wavelength monitoring section. Thesignal and wavelength monitoring section may include (i) at least one ofa set of Mach-Zehnder interferometers or coupled ring resonators, and(ii) at least one flip-chip III-V photodiode. The laser sensor mayfurther include laser drive electronics and a signal processingmicrocontroller. The microcontroller may be configured to (i) controlthe laser drive electronics, (ii) tune currents, and (iii) useinformation from the wavelength and signal monitor section for signalprocessing of the data obtained from the discrete III-V photodiode.

The laser sensor may be configured to perform a wavelength sweep acrossa tuning range as a function of time, and the laser sensor may include aphotodiode configured to convert light reflected from the subject intoan electrical signal.

The fiber-optic interface may be connected to an optical catheter andconfigured to (i) transmit a light signal from the sensor to blood ofthe subject and (ii) transmit reflected light from the blood of thesubject to the sensor.

The fiber optic interface may be in optical communication with beamshaping optics configured to non-invasively illuminate a blood sample ofthe subject through the subject's skin or outer tissue.

In another aspect, embodiments of the invention relate to a method ofmanufacturing a tunable hybrid III-V/IV laser sensor. The methodincludes the steps of (i) manufacturing a III-V semiconductor gain-chip;(ii) fabricating a photonic integrated circuit on a IV-basedsemiconductor substrate by CMOS technology to define a group IVsemiconductor chip; and (iii) hybridly integrating the III-V gain-chipand the group-IV semiconductor chip. The photonic integrated circuit isconfigured to perform wavelength filtering and tuning functions based onVernier effect, and defines an external cavity for the III-V gain-chip.

One or more of the following features may be included. Hybridlyintegrating the III-V gain-chip and the group IV semiconductor chip mayinclude edge-coupling the III-V gain-chip to the group-IV semiconductorchip, actively aligning the two chips, and gluing the two chipstogether.

Hybridly integrating the chips may include flipping the III-V gain-chipp-side down and bonding the gain-chip into a trench defined in thegroup-IV semiconductor chip for edge coupling to the photonic integratedcircuit.

Manufacturing the III-V semiconductor gain-chip may include epitaxiallygrowing a laser layer structure on a substrate by at least one of MBE orMOVPE growth.

The laser layer structure on the substrate may be processed into again-chip device including predefined waveguide angles and contact pads.

The laser layer structure on the substrate may be cleaved into bars. Thebars may be cleaved into a plurality of individual III-V semiconductorgain-chips.

An anti-reflection coating may be formed on an output facet, with powerreflection being less than 0.1% at the output facet. A high-reflectivitycoating may be formed on a back facet, with power reflectivity being atleast 90% or higher on the back facet.

A photonic integrated circuit may be designed according to properties ofthe III-V gain-chip, the photonic integrated circuit comprising at leastone of a spot size converter and a Vernier-filter.

A sensor may include an array of cells, each cell including alaser-based sensor system-on-a chip as described above, each array cellbeing targeted at a different spectral region and a separate targetmolecule.

A wavelength swept laser signal of each array cell may be emitted at adifferent time, and signal collection may be realized by synchronizeddetection with a single photodiode.

The fiber-optic interface may include an out-coupling fiber having acore. An output of the array may be formed by a group of gratingcouplers from the individual array cells routed to a same portion of thesystem-on-a-chip. A total area defined by the group of grating couplersis smaller than a cross-sectional area of the out-coupling fiber core.

The sensor may further include a single output section, a wavelengthswitch configured to switch between outputs of the array cells, and asingle photodiode. An output of the sensor array is formed by the singleoutput section and the wavelength switch. Switching between outputs ofeach individual cell results in a single output of one array cell beingout-coupled to the target at a given time. Signal collection is realizedby synchronized detection with the single photodiode.

The sensor of claim may include at least one array cell is targeted at aspectral region corresponding to at least one peak of water absorptionselected from the group consisting of ˜1460 nm, ˜1900-2000 nm, and ˜3000nm, and (ii) at least one other array cell is targeted at a spectralregion corresponding to at least one absorption peak of a bloodconstituent target molecule.

The sensor of may further include at least one central processing unitprogrammed to determine a water concentration level and a waterabsorption spectrum based on the at least one peak of water absorptionmeasured with the at least one array cell.

The central processing unit may be further programmed to remove abaseline and decompose a complex absorbance spectrum in spectral regionscovered by array cells adjacent to the at least one array cell to revealunderlying target molecule absorption features.

The central processing unit may be further programmed to convert diffusereflectance spectra to absorbance. The absorbance may include acollected absorbance spectrum having a plurality of individualabsorbance spectral components decoupled by using information fromadjacent array cells operating in different spectral regions where nooverlap with other molecular absorption exists. The central processingunit may be further programmed to correct and remove a baseline inspectral regions where absorption spectral features of more than onetarget molecule overlap. The central processing unit may be furtherprogrammed to determine a calibrated concentration level using at leastone of the individual absorbance spectral components. The calibratedconcentration level may be determined based on an individual absorbancevalue and a calibrated attenuation coefficient for each of a pluralityof individual molecules at a given wavelength. The central processingunit may be further programmed to determine a target moleculeconcentration independently of a particular sample volume.

In another aspect, embodiments of the invention relate to a laser-basedsensor system-on-a-chip for real-time monitoring of a blood constituentconcentration level in a subject. The system-on-a-chip includes (i) atunable hybrid III-V/IV laser sensor; and (ii) an optical interfacecoupled to the laser sensor, the interface including beam-shapingoptics. During use, the laser sensor is remote from the subject and theoptical interface is configured to non-invasively illuminate a bloodsample of the subject through the subject's skin or outer tissue.

One or more of the following features may be included. A sensor mayinclude an array of cells, each cell comprising a laser-based sensorsystem-on-a chip including a tunable laser sensor and optical interfaceas described above. Each array cell may be targeted at a differentspectral region and a separate target molecule.

An individual output of each array cell may be focused to illuminate asingle area of the subject, and each reflected signal is collected fromthe illuminated area by the beam shaping optics. The beam shaping opticsmay include at least one optical element, e.g., a lens, a set ofmirrors, and/or a parabolic mirror.

In still another aspect, embodiments of the invention relate to a methodof real-time monitoring of a blood constituent level in a subject,including providing a system-on-a-chip. The system-on-a-chip includes atunable hybrid III-V/IV laser sensor, a fiber-optic interface coupled tothe laser sensor, the surface including a probe, sensor controlelectronics for sensor control and signal processing, and a signalprocessing microcontroller. The laser sensor is disposed remote from thesubject and the probe in optical communication with the subject. Thesystem-on-a chip is instructed to monitor the blood constituent level inthe subject by sending a swept laser signal to the fiber opticinterface. The signal is guided with the fiber optic interface to theblood of the subject. After the signal interacts with the blood, thefiber-optic interface collects a reflected signal from the blood. Thereflected signal is guided to a reflected light photodiode, thereflected signal being an optical signal. The reflected signal isconverted by the sensor control electronics from an optical signal to anelectrical signal. The electrical signal is processed with themicrocontroller to convert the electrical signal into a calibrated bloodconstituent level.

One or more of the following features may be included. The probe may beconnected to at least one of an intravenous optical catheter or anintra-arterial optical catheter for invasive blood analyte concentrationlevel measurement. The optical interface may be attached to the subjectfor non-invasive blood analyte concentration level measurement. Theblood constituent may include or consist essentially of, e.g., lactate,albumin, glucose, ammonia, creatinine, and/or urea.

The various embodiments described above represent individual features ofthe invention which can be applied generally to the system of theinvention. These features may be taken individually as preferredfeatures or more than one of these preferred features may be combinedwith one another in any combination.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A, 1B, and 1C are schematic block diagrams of continuousmonitoring systems for blood analyte concentration level, in accordancewith embodiments of the invention;

FIG. 2 is a schematic diagram of a hybrid III-V/IV system-on-a-chip,including a hybrid widely tunable external cavity laser and laser signaland wavelength monitoring sections, in accordance with embodiments ofthe invention;

FIG. 3A is an experimentally obtained characteristic absorption spectrumof different lactate molecule concentration in a BSA-containing solutionto simulate blood environment, with the spectrum after baselinecorrection, in accordance with an embodiment of the invention;

FIG. 3B is a graph showing the correlation between predicted and reallactate molecule concentration, with predictions obtained usingmultivariate PLS;

FIG. 4 is experimental laser wavelength tuning spectrum obtained for anAlGaInAsSb/GaSb gain-chip based external cavity lasers, in accordancewith an embodiment of the invention, with numbered spectra belong todifferent III-V gain-chips embedded in an external cavity configuration;

FIG. 5 is a detailed schematic block diagram of a III-V/IV widelytunable external cavity laser, in accordance with an embodiment of theinvention;

FIG. 6 is a detailed schematic block diagram of hybrid III-V/IV systemon a chip, in accordance with an embodiment of the invention;

FIG. 7 is an alternative version of a detailed schematic block diagramof a hybrid III-V/IV system-on-a-chip, in accordance with an embodimentof the invention;

FIG. 8 is a schematic cross section of a III-V gain-chip functionallayer structure, in accordance with an embodiment of the invention;

FIG. 9 is a schematic cross section of an exemplary group IVsemiconductor chip having a silicon-on-insulator functional layerstructure, in accordance with an embodiment of the invention;

FIG. 10 is a schematic representation of hybrid integration of a III-Vgain-chip to a group IV semiconductor-based photonic integrated circuit,in accordance with an embodiment of the invention;

FIG. 11 is a schematic representation of hybrid integration of the III-Vgain-chip to the group IV semiconductor-based photonic integratedcircuit, in accordance with an embodiment of the invention;

FIG. 12 is a schematic representation of hybrid integration of the III-Vgain-chip to the group IV semiconductor-based photonic integratedcircuit, in accordance with an embodiment of the invention;

FIG. 13 is a schematic representation of a top view of system on-a-chipphotonic circuitry, in accordance with an embodiment of the invention;

FIG. 14 is a schematic representation of the layout of FIG. 13, withadditional features, in accordance with an embodiment of the invention;

FIG. 15 is a schematic representation of hybrid integration of the III-Vgain-chip to the silicon-on-insulator photonic integrated circuit, inaccordance with an embodiment of the invention;

FIG. 16 is a schematic representation of a fiber probe in the case ofinvasive sensor, illustrating the basic principle of operation based ondiffuse reflection, in accordance with an embodiment of the invention;

FIG. 17 is a schematic representation of a fiber-optic probe in case ofnon-invasive sensing, with the fiber probe 2D cross section is shown forclarity, in accordance with an embodiment of the invention;

FIG. 18 is a schematic representation of forming an array ofsystems-on-a-chip for multiple molecule detection, in accordance with anembodiment of the invention;

FIG. 19 is a schematic representation of synchronized detection using anarray of lasers based on hybrid system-on-a-chip and a single discretephotodiode, in accordance with an embodiment of the invention;

FIG. 20 is a schematic representation of an array of systems-on-a-chipfor multiple molecule detection using a single output fiber and multiplesurface grating couplers, in accordance with an embodiment of theinvention;

FIG. 21 is a schematic representation of an array of systems-on-a-chipfor multiple molecule detection using a single output fiber, awavelength switch, and a single grating coupler, in accordance with anembodiment of the invention;

FIG. 22 is a schematic representation of an array of systems-on-a-chipfor multiple molecule detection using a wavelength switch and a singleend-fire output fiber configuration, in accordance with an embodiment ofthe invention;

FIG. 23 is a diffuse reflectance spectrum of water, obtained by FTIRmeasurement;

FIG. 24 is a diffuse reflectance spectrum of a tris buffer saline (TBS)solution with lactates obtained by FTIR measurement, in accordance withan embodiment of the invention;

FIG. 25 is a processed spectrum in which the TBS spectral component wassubtracted, revealing the spectral component of a lactate molecule, inaccordance with an embodiment of the invention;

FIG. 26 is a simplified block diagram of laser-basedsystem-on-a-chip-sensors configured for non-invasive measurement, inaccordance with an embodiment of the invention;

FIG. 27 is a simplified block diagram of a laser-based system-on-a-chipsensor in which the fiber-optic interface is realized with discrete beamshaping optics for focusing of the optical signal and collecting thediffuse reflection from the subject's blood non-invasively, inaccordance with an embodiment of the invention;

FIG. 28 is a block diagram of an embodiment of a sensor configuration inwhich the sensor includes an array of systems-on-a-chip with individualfocusing optics to illuminate a sample and a single collection lens witha discrete photodiode for reflection signal collection, with thesystem-on-a-chip array being in a linear configuration with thereflected light photodiode, in accordance with an embodiment of theinvention;

FIG. 29 is a block diagram of an embodiment of a sensor configuration inwhich the sensor includes an array of systems-on-a-chip with individualfocusing optics to illuminate a sample and a single collection lens witha discrete photodiode for reflection signal collection disposed in thecenter of the system-on-a-chip array, in accordance with an embodimentof the invention;

FIGS. 30A-30D are transmission spectra of different molecular solutionsmeasured using a widely tunable laser sensor and a reference measurementwith a commercial table-top FTIR spectrometer;

FIG. 31A-31B are spectroscopic measurements made using a commercialtable-top FTIR spectrometer of human blood samples, when the dual corefiber tip is directly dipped into a blood droplet; and

FIGS. 32A-32C are graphs illustrating experimental data obtained withnon-invasive blood measurements via skin made using lasers in accordancewith embodiments of the invention

DETAILED DESCRIPTION

Embodiments of the invention include a hybrid III-V/IV system on-a chipsensor for real-time continuous blood constituent monitoring. Thedescribed embodiments allow the realization of a widely wavelength-sweptlaser-based sensor with wavelength, phase, and power control on a singlechip without any moving parts in the infrared wavelength range fordirect molecular sensing of blood constituents such as lactate, albumin,glucose, ammonia, creatinine, urea, etc. The sensing is performed withdirect laser absorption spectroscopy by scanning the laser wavelengthacross the absorption band of the target molecule. Since thespectroscopic absorption signature is unique to the individual molecule,the described embodiments have an advantage of direct sensing. Thespecific embodiments described below may be used in combination orinterchangeably depending on the context. It is specifically intended inthis disclosure that individual features of the sensor system of theinvention which are disclosed in relation to any of the above figuresmay be considered more generally to represent features of the inventionas a whole. Thus, for example, particular features of the sensordescribed in FIG. 1 may be combined with particular features concerningthe feature of the system on a chip as described in FIGS. 18, 20, 21 and22. Similarly, for example, particular features of the sensor describedin FIG. 1 may be combined with particular features concerning theIII-V/VI chip as described in FIGS. 5 to 12 etc. Likewise, particularfeatures of the system on the chip may be combined with particularfeatures of the III-V/IV chip architecture etc.

Hybrid semiconductor technology is used, in which the active gain mediumis realized in a III-V semiconductor structure in the form of again-chip or semiconductor optical amplifier that is coupled to apassive photonic integrated circuit realized on a group IV-basedsemiconductor substrate such as silicon, silicon-on-insulator (SOI),germanium-on-insulator (GOI), germanium on silicon, silicon nitride onsilicon, silicon nitride-on-insulator, siliconnitride-on-silicon-on-insulator. The group IV technology uses processesthat are standard industrial CMOS fabrication steps used in themicroelectronics industry and allow realization of photonic integratedcircuits based on group IV materials and their derivatives. Thisapproach enables the described sensor technology to be scalable,very-low form factor, low-cost, and applicable to mass marketapplications such as personalized health monitoring, athletics by meansof wearable technology or individual patient health monitoring byentering a clip-on non-invasive bedside system. Further, accuratesensors can provide valuable information by entering a fiber-optic baseintravascular optical catheter or other invasive probe for directcontact to patient's blood.

Embodiments of the invention include a laser sensor including a photonicsystem-on-a-chip, a fiber-optic interface for signal delivery andcollection of reflected light, a reflected signal photodiode, and adigital signal processor for sensor control and signal processing (seeFIGS. 1A-1C and related discussion).

The photonic system-on-a-chip includes a widely wavelength-tunable lasercavity, with, e.g., an AlGaInAsSb broadband gain-chip designed to emitin 1800 nm-3500 nm wavelength range edge-coupled to a group IVsemiconductor based photonic integrated circuit in which wavelengthtuning, filtering, monitoring and out-coupling are realized (seediscussion below with respect to FIG. 2).

The sensor principle is based on tunable laser absorption spectroscopy,with a laser wavelength sweep performed across a spectral range wheremolecular absorption bands due to rotational-vibrational states of themolecule are present. The wavelength is absorbed by the vibration of thetarget molecule leading to a change in the reflected signal(photon-phonon interaction). The wavelength is swept as a function oftime. Therefore, spectral information is recovered by a single detectorin contrast to prior art methods, such as the methods disclosed in U.S.Patent Publication No. 2012/0226118. In addition, wavelength and signalcontrol sections enable knowledge of the laser wavelength tuning curveat all times and allow discrimination between system-based distortionsfrom sample-based distortions.

In embodiments of the invention, light with known properties (exactwavelength, power and tuning curve) is generated and may be coupled to afiber through which the light is coupled onto a sample—either directcontact of fiber probe tip to blood containing the molecule of interestor through skin towards blood containing vessel/tissue.

As discussed below with respect to FIG. 3, by choosing the correct laserdesign, the laser emission spectrum can be chosen to selectively targeta molecule of interest. For example, the molecule of interest may be alactate molecule, which has distinct spectral absorption bands relatedto C—H and O—H molecular stretch vibration overtone combination bandsaround 2260 nm and 2300 nm. Depending on the application requirements,the external cavity laser needs to be designed to have a laser tuningbandwidth >50 nm to recover the shape of the specific absorptionfeature.

As discussed with respect to FIG. 4, the disclosed laser-based sensorshave the ability to sweep wavelengths across a bandwidth of 50 nm ormore at a rate of 10 Hz to several kHz range and allow for real-timemonitoring. AlGaInAsSb based gain-chips offer gain-bandwidth in excessof 150 nm and can be designed to target any central wavelength within1700-2500 nm by changing the epitaxial layer design. Other materialssuch as AlGaInAsP and AlGaInAsSbP can be used to further broaden thewavelength coverage from 1000 nm-3500 nm and beyond. The wavelengthselection, tuning and monitoring is realized in the group IVsemiconductor based photonic integrated circuit chip.

In the described embodiments, the wavelength tuning requirement enableswavelength sweep across several tens of nm at a rate up to several kHz.This is achieved by enabling an external cavity to form a Vernier-filterin which coupled resonators with slightly different free-spectral rangevalues are coupled together. A discussion of theory on Vernier tuningand different ways of achieving it may be found in, e.g., J. Buus, M.-C.Amann, D. J. Blumenthal, Tunable Laser Diodes and Related OpticalSources, 2^(nd) Edition, John Willey & Sons, Inc., 2005. The disclosureof this document and in particular the principles described therein arespecifically incorporated by reference herein in its entirety and areintended to form part of this disclosure.

The maximum tuning range of such Vernier-filter laser is limited by thefree-spectral range of the Vernier filter:

$\begin{matrix}{{\Delta\lambda} = \left| \frac{{{FSR}1} \cdot {{FSR}2}}{{FSR1} - {FSR2}} \right|} & \left( {{Formula}\mspace{14mu} 1} \right)\end{matrix}$

where FSR1,2 is the free-spectral range of the first and secondresonators, respectively. The transmission function of such filter has amaximum where the resonant peaks of individual resonators overlap,determining the laser emission wavelength. The wavelength is swept byapplying heat and/or current to at least one of the resonators, whichinduces a refractive index change and therefore the transmission overlapposition. In other words, changing the effective refractive index of aresonator effects a change in a wavelength of a laser generated by thegain-chip. Such a filter can be realized by a combination of coupledmicro-ring resonators with different cavity lengths or sampled-gratingdistributed Bragg reflector (DBR) designs. See, e.g., U.S. PatentApplication Publication No. 20040228384 to Oh et al., which isincorporated by reference herein in its entirety and the fabricationsdescribed in this disclosure are specifically intended to form part ofthe present disclosure.

As discussed with respect to FIG. 5, the widely tunable external cavitylaser may include a III-V (AlGaInAsSb, AlGaInAsP, AlGaInAsSbP,AlGaInAsNSbP, etc.) gain-chip, spot-size mode converter, phase-shiftsection, coupled resonators with different free-spectral range values, awide band reflector or reflectors and individual electro-thermal heatersfor each of the resonators and phase shift section. For calibration-freeoperation, a laser signal emitted from the external cavity laser ispassed through a beam-splitter.

As shown in FIG. 6, an exemplary beam-splitter is a 1×2 Mach Zehnderinterferometer (MZI), where one arm is coupled to either a surfacegrating coupler for surface out-coupling or spot-size mode converter andend-fire coupler (edge out-coupling) to couple to a fiber-opticinterface, while the second arm of the MZI is used to pass the signal toa wavelength and signal control section realized by adding an additionalfilter in the form of for instance imbalanced 1×2 MZI with known opticalpath difference and with a photodiode at each of the arms to provide anoscillating transfer function which can be used to recover the emissionwavelength and wavelength shift of the laser at any given moment of timethus providing calibration-free operation of the laser sensor.

As discussed with respect to FIG. 7, similar wavelength control can alsobe realized by a single coupled ring resonator, whereby signal andwavelength control can be recovered by monitoring the filters'transmission function with a single photodiode.

In both embodiments of wavelength control, the system-on-a-chip iscontrolled by drive electronics, which in turn are controlled by amicroprocessor that takes into account the data received from thewavelength control, and signal control and reflected signal photodiodes,and adjusts the drive parameters accordingly. This ensures that thelaser wavelength sweep function is known and can be accounted for whenprocessing the reflected light signal. The reflected light signal isprocessed using a developed algorithm that enables conversion ofphotodiode time signal into spectral domain to recover blood constituentconcentration level data.

The fiber interface used for the sensor includes at least two separatecores, with one core (signal core) being used to transmit the lasersignal from the sensor to the sample and the second core (collectioncore) being used to collect the reflected light from the sample andguide it to the photodiode at the sensor. Light can be coupled in andout of the system-on-a-chip by a surface grating coupler or anedge-coupled via end-fire configuration. In both cases the fiber corecan be either multimode or single-mode.

Referring now to FIG. 1A, in an embodiment of the invention, alaser-based sensor includes a hybrid III-V/IV photonic system-on-a-chip(SoC) 10, which includes a widely tunable laser and a laser wavelengthand amplitude monitoring section with flip-chip bonded, glued, transferprinted, or edge coupled integrated photodiodes. The sensor alsoincludes an optical interface, such as a fiber-optic interface 20 forsignal delivery via an optical communication link such as a fiber 12 andcollection of reflected light via an optical communication link such asfiber 31, and a reflected signal (light) photodiode 40. Accordingly, theSoC includes at least one photodiode for wavelength/power monitoring,and another discrete photodiode for monitoring a signal reflected fromblood. These components are described in greater detail below.

In addition to an optical interface, the sensor includes an electronicinterface that is responsible for sensor control and signal processing.Generally, the sensor's control electronics include a central processingunit (CPU) 50, amplifier and analog-to-digital converter section 52,driver and digital-to-analog converter section 53, and a power supplyelectronics section 54 that supplies power for all electronic andphotonic components. A suitable microcontroller for use with embodimentsof the invention is an STM32F100 from STMicroelectronics, MSP430 fromTexas Instruments, or other similar microcontrollers.

Since the CPU 50 is able to process only digital signals, whereas theSoC 10 and reflected signal photodiode 40 inherently provide analogsignals, additional interfaces for converting digital signals to analog53 and analog signals to digital 52 are needed. Based on the signalreceived from the SoC 10, via the electrical interface 51 that passesthrough the analog-to-digital converter section 52, the CPU 50 controlsthe drive signals of the SoC 10 via interface 15. Drive signals includegain-chip drive current, heater currents, photodiode bias, etc. Thedrive signals of the CPU pass through digital-to-analog convertersection 53 that converts them to a form acceptable by the SoC and itselements. In addition, the CPU is in electrical communication with thepower supply electronics section 54 via electrical interface 546 to setthe necessary power supply values to remaining sensor elements viaelectrical interfaces 541, 542, 543, 544. Such a control scheme allowsthe CPU to precisely control the SoC and monitor the output signal inreal-time. Thus, when the light signal out-coupled from the sensorinteracts with the target molecule in blood is modified due to theinteraction and is reflected back via fiber-optic interface 20 andguided to discrete reflected light photodiode 40, the collected signalis amplified and converted to digital form by the analog-to-digitalinterface 52 via electrical interface 41 and processed by a CPU torecover spectral and intensity information based on the comparison withthe out-coupled signal. Signal processing includes conversion of timesignal into wavelength/frequency domain and application of dataprocessing algorithm specific to the target molecule. This allows therecovery and evaluation of the concentration level of the targetmolecule and provides as digital output via electrical interface 56 toan output display 60 that converts the signal to calibrated units suchas mmol/l or g/l.

In the described embodiment, the photonic system-on-a-chip 10, reflectedsignal photodiode 40, and electronic components CPU 50,analog-to-digital interface 52, digital-to-analog interface 53, andpower supply electronics section 54 are remote from a subject 30 and theinteraction is by means of optical communication via the fiber-opticinterface 20, which also includes a probe.

As used herein, a probe is a fiber optic device having at least twofiber cores, with one core suitable for use for the delivery of thelaser signal to a sample and the other core suitable for detection ofreflected light from the sample. In the case of an invasive measurement,the fiber optic interface needs to connect to an intravascular opticalcatheter that contains, among other probes, at least two optical fibercores that connect to the SoC fiber interface in order to transfer andcollect the sent and reflected laser signals. The two fiber cores of theprobe terminate at the distal end which, in use, is in direct contactwith blood. The terminated fiber core tips act as apertures throughwhich the light is delivered to blood and collected thereafter. In thecase of non-invasive measurement, the probe also has a distal end that,in use, is in direct contact to outer skin/tissue, with the fiber coreapertures used to deliver and collect light through the outer tissue.

In use, the photonic system-on-a-chip 10 is driven and controlled by theembedded microprocessor CPU. The system-on-a chip 10 is instructed tosend a swept wavelength laser signal to the fiber optic interface 20,with the laser signal consisting of a wavelength vs. time sweep. Thelaser signal is coupled to the fiber optic interface 20 that guides thesignal to a target object device under test (DUT) 30, which in theillustrated embodiment is blood of a living body.

The laser signal interacts with the blood of the living body and ismodified as a result of this interaction which provides characteristicfeatures in the signal reflected from the blood. The reflected lightsignal is collected via fiber-optic interface 20, and is guided back tothe reflected light (signal collection) photodiode 40. The photodiode 40converts the optical signal into an electrical signal. The time domainsignal is processed by the CPU, which takes into account the propertiesfrom the photonic SoC and the data analysis algorithm, and converts thephoto diode signal into a calibrated concentration level in mmol/l(i.e., a blood constituent level), and provides as an analog or digitaloutput via an electrical interface 56.

FIG. 1B shows an embodiment in which a probe is connected from thefiber-optic interface 20 to an optical intravascular catheter orinvasive probe 22, which is in physical contact with the target object30. The catheter 22 is configured to (i) transmit a light signal fromthe sensor to blood of the subject and (ii) transmit reflected lightfrom the blood of the subject to the sensor.

FIG. 1C shows an embodiment in which the optical interface, consistingof the light delivery and light collection cores and additional optics,e.g., beam shaping optics, is configured to non-invasively illuminate ablood sample 30 of the subject through the subject's skin or outertissue 23. One may preferably put the non-invasive probe at a locationwhere the outer tissue has a relatively small thickness such asfingertip, fingernail bed, wrist, etc.

Referring to FIG. 2, the photonic system-on-a-chip 10 includes a III-V(e.g., AlGaInAsSb/GaSb or AlGaInAsP/InP or AlGaInAs/GaAs) semiconductorgain-chip 211 that provides optical gain to the system. The gain-chip211 is coupled to a passive photonic integrated circuit realized in agroup IV semiconductor chip, in the particular case silicon-on-insulatoris chosen. A typical photonic circuit 220 includes a spot-size converter212 that increases the efficiency of light coupling between the chips.The typical photonic circuit also includes a wavelength filteringsection 213 that forms a hybrid III-V/IV external cavity laser whencombined with the III-V gain-chip 211. The photonic integrated circuit220 also includes a signal/wavelength monitoring section 214 and asignal outcoupling section 215, discussed in more detail with respect toFIGS. 6 and 7 below.

The wavelength filtering section 213 is preferably realized by coupledresonators and wideband reflector forming a Vernier filter. The coupledresonators have different free-spectral range values, which whencoupled, lead to a wide accessible bandwidth. For example, a coupledresonator cavity may be formed from two micro ring resonators: a firstring with a ring radius of 27.5 microns and the second ring resonatorwith radius of 28.5 microns. For a GaSb material system at an operatingwavelength of 2300 nm, the effective modal refractive index is 3.59.This leads to a free-spectral range of the first ring resonator being4.26 nm and a free-spectral range of the second ring resonator of 4.11nm. When coupled, the Vernier filter has a tuning bandwidth of 117 nm.These values may be calculated by use of the following equations.

In case of a ring resonator, the mode spacing can be defined as:

${FSR} = \frac{\lambda^{2}}{4{\pi{nR}}}$

where λ is the center wavelength, n is the modal effective refractiveindex and R is the ring radius.

The overall tuning bandwidth can be estimated by

${\Delta\lambda} = \left| \frac{{{FSR}1} \cdot {{FSR}2}}{{FSR1} - {FSR2}} \right|$

The tunable bandwidth can be adjusted by design in the form of differentfree-spectral range offset and coupling coefficient. Such a bandwidth issufficient to be coupled to a broadband III-V gain-chip to cover thenecessary spectral range for blood metabolite concentration levelmonitoring.

A lactate molecule is a good example of a target molecule both in termsof application significance as well as a well-expressed opticalsignature in the infrared range. FIG. 3A illustrates an experimentalabsorption spectrum of a lactate molecule. It can be clearly seen thatdue to the liquid phase of the target, the spectrum is broad andfeatures two distinct absorption peaks, centered at 2260 nm and 2300 nm.For concentration level calculation, it is beneficial to have the shapeof the absorption signal. Also, as can be seen from the same figure, inthe case of a lactate molecule, the accessible optical bandwidth neededis about 100 nm. An experimental concentration calibration curve fordifferent concentration levels is shown in FIG. 3B.

Besides the passive circuitry optical response, it is necessary that theoptically active part be capable of covering the needed bandwidth. Atypical wavelength tuning spectrum of a mid-infrared broadbandgain-chip, realized, for example, in an AlGaInAsSb/GaSb materialplatform can have an optical gain-bandwidth in excess of 170 nm, asshown in FIG. 4. Each of the spectra 400, 410, 420, 430, 440 wasgenerated by a different III-V gain-chip embedded in an external cavityconfiguration. The spectral position of the gain-chip emission can betuned by chip design by changing the layer thicknesses and compositionsto match the necessary spectral response of the target molecule and theoptical response of the photonic integrated circuitry on the group-IVsemiconductor chip, using methods known to one of skill in the art. FIG.4 clearly demonstrates the flexibility of III-V chip design in theentire 1700 nm-2500 nm range without trade-off in performance.

Referring to FIG. 5, a hybrid III-V/IV widely tunable external cavitylaser 500 includes a III-V, in this particular case, AlGaInAsSb/GaSbgain-chip 501 that may serve as an active optical medium and may beedge-coupled to a silicon photonics integrated circuit 520 via the spotsize converter 502 that converts the mode emitted from the gain-chip andmatches it to a size suitable for the group-IV semiconductor basedwaveguide used in the photonics integrated circuit. Wavelength tuning isrealized by means of Vernier-effect filter 530, where fine tuning iscontrolled with a phase control section 531 that may include a straightor folded waveguide section with a separate electro-thermal heater 5311.The wide tuning is controlled by the coupled-resonator cavity, where afirst resonator 532 with a free-spectral range of FSR1 is coupled to asecond resonator 533 with a free-spectral range FSR2, where FSR1 andFSR2 are non-equal. The effective modal refractive index of each of theresonators is controlled individually via electro-thermal heaters 5321and 5331. The laser resonator cavity is completed with a widebandreflector 534 that is designed to be broad enough for the requiredtuning range. Typically the reflector has a reflectivity bandwidth inexcess of 50 nm or more. The reflector may be realized by, e.g., adistributed Bragg reflector or a folded Mach-Zehnder interferometer(MZI) or any other typical broadband reflector—such as metal mirror. Fora typical operation performed by the sensor, the gain-chip drive currentis fixed, and the wavelength sweep is performed by a controlled sweep ofthe heater 5311, 5321, 5331 currents.

Vernier wavelength filtering technique is well known in the field ofoptical communications and is not limited to micro-ring resonators butcan also be realized by coupled resonators defined by sampled gratingdistributed Bragg reflectors or sampled grating distributed feedbackreflectors. The final choice depends on the designer's preferences andgeometrical considerations of the chip layout. In all cases of coupledresonators, the wavelength of operation is defined by the overlap of thetwo wavelength combs. The overlap position is changed by changing therefractive index of one or both coupled resonators simultaneously. Inpractice, this is achieved either by direct current injection or thermalheating causing a change of refractive index and thus emissionwavelength. In the described example, a change in wavelength iscontrolled by deposited resistive heaters above each micro-ringresonator. Wideband reflector can be realized in the form of distributedBragg grating, a folded balanced Mach-Zehnder interferometer or asimilar high-Q reflector. Preferably, the tuning band of the system isdefined by the bandwidth of either the Vernier filter or the widebandreflector, depending on which of the two is smaller.

Referring to FIGS. 6 and 7 as well as to FIG. 2, wavelength and laserpower monitoring of the external cavity laser formed by the gain-chip211 and the wavelength filter 213 can be realized in the form of anon-balanced Mach-Zehnder interferometer with each output coupled to aseparate grating coupler with an integrated photodiode (flip-chip,glued, etc.) or a single-ring resonator coupled to a grating couplerwith an integrated photodiode. This is called a signal/wavelengthmonitoring section 214. Both the non-balanced MZI and a single ringresonator have a very well defined wavelength dependent transmissionfunction, which can be characterized and calibrated to provide an exactvalue of emission wavelength and output power at any given moment oftime, presuming the drive signals are known. This is advantageous, asboth signal power and signal wavelength can be tracked via a singlephotodiode with high accuracy. Thus the described combination of ahybrid system-on-a-chip includes not only a widely tunable laser butalso a monitoring wavelength meter and power meter within the same chip.

Referring to FIG. 6, more specifically, the hybrid III-V/IV widelytunable external cavity laser 500 described in FIG. 5 is coupled to a1×2 Mach-Zehnder interferometer (MZI) splitter 600, where one arm isused to out-couple the laser signal to the system-on-a-chip out-couplingsection 641 either via top grating coupler or mode-size converter andend-fire out-coupler 6412 which further out-couples light to thefiber-optic interface. The second arm of the 1×2 MZI splitter 600 isconnected to a second 1×2 MZI 642, which is non-balanced. One arm of theinterferometer is connected to a grating coupler 6421 which guides thelight into a flip-chip bonded photodiode 64211 for laser signalmonitoring. The second arm of the interferometer is guided to a secondgrating coupler 6422, which couples light into a second photodiode64221, which monitors the MZI 642 transfer function for precisewavelength tracking.

The drive signals for the gain-chip, individual heater tuning, and phaseshift tuning are controlled by the CPU 5, which uses the informationfrom the signal/wavelength monitoring section photodiodes to determinethe necessary driving signal form and amplitude. A typical SoC mayrequire that at least five different control currents be accounted forto generate a continuously tunable wavelength laser pulse. In thedescribed embodiment, a CPU provides a drive signal sweep that consistsof a certain sweep of individual drive currents for the SoC, to providea continuous wavelength sweep as a function of time at the sensoroutput. Since the CPU is in electrical communication with SoC signal andwavelength monitoring section photodiodes 64211 and 64221 at all times,generally any arbitrary drive signal results in SoC output that can berecovered in terms of amplitude and wavelength at all times. In a realcase scenario, the CPU may be programmed to provide the simplestpossible signal output—for example as close to a linear wavelength sweepas a function of time as possible—to enable simple data processing basedon the recovered signal from a discrete photodiode 40. Knowledge of thelaser signal amplitude and wavelength within the sent light pulse allowssimple reconstruction from time to frequency domain of the collectedsignal from the blood and elimination of the nonlinearity and signalvariation due to the sensor itself, in such way allowing direct accessto the perturbation of the optical signal due to interaction with thetarget molecule.

Referring to FIG. 7, in another embodiment, the hybrid III-V/IV widelytunable external cavity laser 500 described in FIG. 5 is coupled to a1×2 Mach-Zehnder interferometer (MZI) splitter 600, where one arm isused to out-couple the laser signal to the system-on-a-chip out-couplingsection 641 either via top grating coupler or mode-size converter andend-fire out-coupler 6412 which further out-couples light to thefiber-optic interface. The second arm of the 1×2 MZI splitter 600 iscoupled to a ring-resonator 742, which provides a characteristicwavelength transfer function for the light that passes through. Afterthe filter the light is guided to a grating coupler 7422 which coupleslight to a flip-chip photodiode 74221 which monitors the signal transferfunction. The transfer function can be used to determine the wavelengthof the light and relative intensity of the laser at the same time, withonly one control photodiode, rather than multiple photodiodes as, forexample, illustrated in FIG. 6.

In the described embodiments, a hybrid integration of III-Vsemiconductor chip and group-IV semiconductor chip technology isconsidered. The gain-chip is realized in a III-V material system such asAlGaInAsSb/GaSb, AlGaInAs/GaAs or AlGaInAsP/InP or a combinationthereof, in the form of an edge emitting device such as ridge waveguideedge emitter. The light is generated by electrical injection of carriersinto the undoped quantum wells where they recombine emitting photons.The optical gain for such a structure is spectrally broad and typicallycan span from few 10s of nm to 200 nm or more depending on the photonenergy ant the epitaxial design. The spectral region can be defined bychoosing appropriate layer alloy compositions and thicknesses, as iswell known by those skilled in the art of semiconductor optoelectronics.

A typical schematic cross-section of a III-V gain-chip 800 is shown inFIG. 8. A III-V gain-chip is epitaxially grown on a III-V substrate 810that, depending on the desired wavelength of operation, can be GaAs,InP, GaSb, or InAs. On top of the substrate, the remaining structurallayers are grown, i.e., a lower cladding layer 820, lower waveguidelayer 830, quantum-well based active region 840, followed by a more orless symmetric upper waveguide layer 850, and upper cladding layer 860.The layers may be grown epitaxially, e.g., by molecular beam epitaxy(MBE) or metalorganic vapor phase epitaxy (MOVPE). The structure isfinalized by a highly doped contact layer 870 that forms an ohmiccontact with the top metal contact layer 880. The bottom contact layeris formed by a metal layer deposited on the bottom of the substrate 805.The emission wavelength is defined by the composition of layer 840. Thestructural layers 820, 830, 850 and 860 are chosen to providesymmetrical wave-guiding and good optical mode overlap with the activeregion layer 840. Typically, the active region is composed of at leastone quantum well to provide sufficient gain.

To form the gain-chip, the epitaxial structure is processed into aridge-waveguide edge-emitting device, in which mode is guided by adefined ridge waveguide formed by plasma or wet-etching. The height andwidth of the ridge depends on the individual design, an importantfeature being that the waveguide is single mode. The design of singlemode waveguides is a common procedure and is known to those skilled inthe art. The cavity of the gain-chip may be realized by cleaving theprocessed wafer into bars, consisting of a linear array of edge-emittinggain-chips, with the cleaved crystal facet forming a cavity mirror, asis common in making edge emitting devices such as semiconductor lasers.The optical emission is from the edge of the chip, i.e., perpendicularto the growth direction.

For optimal performance in external cavity laser configuration, the backfacet may be coated with a high-reflectivity mirror coating, with atypical mirror reflectivity of at least >90%, e.g., >95%. The frontfacet, i.e., the output facet, of the chip is preferably coated withvery low reflectivity coating, with typical reflectivity of <0.1%, toavoid optical feedback from the front facet plane. Optical feedback maybe further reduced by using a bent waveguide design in which the ridgeof the gain-chip has a predetermined bending radius to reducereflection. Due to the bending of the ridge, the out-coupled light isrefracted and emission is at a fixed angle in terms of the output plane.This predefined waveguide angle is known from the design and modaleffective refractive index, and needs to be taken into account whendesigning the passive photonic circuitry on the group-IV semiconductorplatform. In particular, the spot-size converter is preferably designedto match the angle of the gain-chip emission and the size of theoutcoupled mode to reduce coupling loss between the two chips.

For best design practice, the main properties such as mode size andshape, emission wavelength, gain-bandwidth, emission angle, divergence,etc. of the III-V gain-chip are known experimentally and are used toadapt and customize the passive photonic integrated circuit on group-IVsemiconductor. In particular, knowing the experimental parameters of thegain-chip allows optimizing main SoC elements such as spot-sizeconverters, coupled resonator cavities, wide band reflectors, multimodeinterference devices (MMI), interferometers, and other functionalelements.

Typically, facet coating is performed on gain-chip bars, and individualgain-chips are separated by scribing and breaking after the facetcoating procedure. This can be done in many ways, with the most commonbeing forming a mechanical scribe line along the crystal planeperpendicular to the chip cleaved facets and applying mechanicalbreaking force from the top or bottom to enable crystal cleavage alongthe defined line. Individual gain-chips can then be readily integratedwith the group-IV circuitry.

A group IV-based semiconductor platform is typical for most commonelectronic device technologies such as CMOS. Hybrid integration of III-Voptical components with a group IV semiconductor platforms opensopportunities for scaling technology in the same manner as CMOStechnology is scaled. Group IV semiconductor platforms include silicon,silicon-on-insulator (SOI), germanium-on-insulator (GOI), germanium onsilicon, silicon nitride on silicon, silicon nitride-on-insulator,silicon nitride-on-silicon-on-insulator, and their derivatives.

A typical silicon, in particular a silicon-on-insulator (SOI) chipcross-section is shown in FIG. 9. In the illustrated embodiment, the SOIchip 900 is simpler than the gain-chip and includes a IV-basedsemiconductor substrate 905, e.g., a silicon substrate with a buriedoxide layer (called BOX) 910 which can be of different thicknessesdepending on the fabrication facility, with typical thicknesses being2-3 microns. The BOX layer is formed by, for example, ion implantationand wafer bonding, as is well known to one of skill in the art. The BOXlayer 910 is followed by a silicon waveguide layer 920. This layerserves as a functional layer where all passive photonic components arerealized, such as grating coupler, single-mode and multimode waveguides,ring resonators, multimode interference devices, spot-size converter,etc. The layer thickness may vary depending on the fabrication facility,and is typically 100 nm-500 nm thick; in some fabrication facilities itcan be as thick as several microns. A typical silicon photonics platformincludes a 220 nm waveguide layer 920. The waveguide layer 920 isfurther capped with a silicon oxide layer 930 that can be thermallygrown or deposited by other techniques. Depending on the group-IVplatform used, other insulating materials can be used, for examplesilicon nitride. The main purpose of the BOX layer 910 is to preventoptical mode coupling from the waveguide layer 920 into the substrate905 and to serve as a low refractive index cladding layer in the samemanner as the top silicon oxide layer 930. The refractive index changeof the silicon waveguide layer 920 can be achieved by thermal signal viathe resistive electrical heaters in the form of metal electrodes 940deposited on top of the upper oxide layer. In addition to heaters, themetal electrodes can also serve as flip-chip photodiodes that collectthe signal out-coupled from the grating couplers.

A schematic principle of hybrid integration is shown in FIG. 10. Herethe III-V gain-chip 800 and the group IV semiconductor, in theparticular example silicon-on-insulator chip 900 are integrated byedge-coupling, with the III-V gain-chip being p-side up and edge coupledto the group IV chip. The light generated in the active region layer 840of the gain-chip is coupled to a silicon waveguide layer 920 wherepassive photonic integrated circuitry is realized. One of the criticalrequirements for the integration is efficient coupling of light betweenthe two chips. This can be achieved by using active alignment technique,i.e., with the III-V gain-chip emitting light during the alignmentprocess and the coupling efficiency monitored via a grating coupler onthe group IV chip. Once the signal is maximized, the two chips arebonded together by curable glue or epoxy.

A higher accuracy can be achieved when the position of the III-Vgain-chip is predefined on the group-IV semiconductor wafer. This can berealized by a deep trench as shown in FIG. 11. The trench 1100 not onlydefines the approximate position but at the same time can exactly matchthe height of the two chips in the vertical direction. For maximumaccuracy the III-V gain-chip needs to be flipped so that the height ofthe III-V chip is defined by the epitaxial layer thickness, which isextremely accurately controlled. The in-plane position needs to bealigned via active alignment for best accuracy. The chips are fixedtogether by means of glue, epoxy or metal solder such as indium or AuSnat the interface between top metal contact layer 880 and metal electrodelayer 940. The illustrated III-V gain-chip is flipped to a p-side downposition, and edge coupling is realized via the pre-defined trench inthe group IV wafer that enables light coupling to the passive photoniccircuitry.

A complete hybrid system including a III-V gain-chip, group IVsemiconductor chip, and flip-chip photodiode is shown in FIG. 12,demonstrating how light can be coupled into the group IV semiconductorchip and coupled out of the group-IV semiconductor chip. The III-Vgain-chip is flipped to p-side down position and edge coupling isrealized via a pre-defined trench in the group IV semiconductor wafer toenable light coupling to the passive photonic circuitry. A flip-chipphotodiode structure is also shown, used to collect optical signals viaa surface grating coupler.

In particular, coupling out is achieved via a flip-chip photodiode ontop of a grating coupler 950. The photodiode can be formed from anyrelevant semiconductor material that has a needed photo response at thewavelength of interest. In this embodiment, a typical photodiode is aIII-V p-i-n photodiode designed from the same material platform as theIII-V gain-chip. The photodiode 1200 is formed on a III-V substrate1205, followed by a doped layer 1210 that is either n or p-type, undopedabsorption layer 1220 having an undoped material composition such thatit absorbs the light coupled out of the group IV semiconductor chip. Theabsorption layer thickness is optimized for different wavelengths, witha typical thickness of 2 microns and a typical minimum thickness of atleast 500 nm. The absorption layer is followed by a doped layer 1230that can be either p- or n-type but needs to have a dopant polarityopposite to that of layer 1210 in order to form a pn-junction. The anodeand cathode are preferably realized on the same side of the chip tofacilitate flip-chip process. In the exemplary figure, the doped layer1210 is biased by etching a trench and depositing a metal layer 1250 toform a metallic ohmic contact. Suitable metals include titanium,platinum, gold, nickel, chromium, and gold-germanium and/or combinationsthereof, as is well-known to those skilled in the art. The metal layer1250 is in contact with the doped layer 1210 only at the bottom of thetrench. Other photodiode layers are separated from the metal layer by adielectric isolator 1240. The second contact is formed on top of thephotodiode diode mesa and is to have an ohmic like contact between thetop metal pad 1260 and the top contact semiconductor doped layer 1230.The photodiode is coupled to the photonic integrated circuit withflip-chip technology as follows. The photodiode is flipped aperturefacing down and overlapping with a portion of the surface gratingcoupler formed on the group IV semiconductor chip. The photodiode isaligned for maximum signal collection coming out from the gratingcoupler and bonded in place by means of indium, AuSn or other standardsoldering techniques.

Top views of the schematic hybrid system-on-a-chip based onedge-coupling are shown in FIGS. 13 and 14. A III-V gain-chip 800 isedge coupled to a group IV semiconductor chip via spot-size converter1300 that converts the mode size from the III-V waveguide to the siliconwaveguide with minimal optical loss. The spot size converter is coupledto a phase shift section 1310 consisting of a straight or foldedwaveguide and an electrical heater. This section is used to preciselycontrol the emission wavelength within a narrow spectral range withoutmode-hops. The phase section is further connected to a coupled resonatorcavity defined by two micro ring resonators 1320, 1330 having slightlydifferent cavity lengths and thus different free-spectral ranges. Thecoupled micro ring resonator cavity is closed with a wide band reflector1340. In the embodiment illustrated in the figures, the wide-bandreflector 440 is represented as a folded (closed-loop) 2×2 Mach-Zehnderinterferometer (MZI). The combination of features 800, 1300, 1310, 1320,1330 and 1340 form a widely tunable external cavity laser. This externalcavity is connected to a 1×2 Mach-Zehnder interferometer 1350, where onearm is used to out-couple the laser signal from the system-on-a-chip viaa grating coupler 1380 which is connected to an optical fiber interface.In order to know the laser wavelength and signal intensity at all times,the wavelength/signal monitoring section 1360 is connected to the otherarm of the 1350 1×2 Mach-Zehnder interferometer.

In FIGS. 13 and 14, the wavelength/signal monitoring section 1360 isshown as a non-balanced 1×2 Mach-Zehnder interferometer—where theoptical path of the upper arm is different from that of the lower arm.Both outputs are connected to separate surface grating couplers 1390 and1395 that are used for system power and wavelength tracking. Thesegrating couplers are coupled to flip-chip photodiodes bonded on topdirectly. In general it is also possible to add additional gratingcouplers 1370 to monitor optical signal within different sections of thesystem-on-a-chip. In the illustrated example, grating coupler 1370 isused to monitor the optical signal from the gain-chip after the firstmicro ring resonator.

The described system-on-a-chip is further controlled by electricalsignals in the form of resistive heaters as shown in FIG. 14. Here, theheater 1400 is used for constant phase shift control of the tunablelaser. Heaters 1410, 1420 are used to control the lasing wavelength ofthe coupled micro ring cavity and to control the wavelength change.Heater 1440 is used to control the reflectivity of the widebandreflector, and heater 1430 is used to control the optical signalsplitting ratio between the upper and lower arms of the 1×2 MZI 1350.The heaters are connected to contact pads 1450 on one side of the chip,which is typically opposite the side where the grating couplers arerealized. Drive signals are controlled by a microprocessor, where thecomplete signal processing takes place.

Referring to FIG. 15, a hybrid system on a chip can also be realizedcoupling the III-V gain-chip to the group IV semiconductor chip via asurface grating coupler instead of edge-coupling. Here, the gain-chip800 is bonded to the submount, which can be a ceramic or metal carrier1500, and pre-aligned with collimation lens 1510 and reflector prism1520, forming a micro-optics bench. The entire assembly is then alignedover the grating coupler 950 and fixed to a top surface of the group-IVsemiconductor chip 900 with solder or epoxy. The light from thegain-chip is collected via collection and collimation optics 1510 andreflected into a surface grating coupler via a prism or a mirror 1520.The grating coupler couples the reflected light into a silicon waveguide920, where the remaining portion of the system-on-a-chip is realized.While this hybrid integration is typically more straight-forward, anedge-coupling configuration may generally be more efficient.

In an embodiment, the laser signal from a system-on-a-chip is coupled toa fiber-optic interface via a grating coupler, such as the gratingcoupler 1380 illustrated in FIG. 13. The fiber optic interface mayconsist of an optical fiber, i.e., a fiber probe, through which thelight is guided from the sensor to a probe tip that is in opticalcommunication with the target, e.g., the blood of the patient. In thecase of an invasive measurement, the fiber probe may include two fibercores and connect to an optical catheter that enters the vein or arteryof a patient.

A catheter probe 1600 in direct contact with blood is shown in FIG. 16.Here, the probe 1600 includes at least two fiber cores. A first core1610 is used to transmit light from the system-on-a-chip that is outsideof the human body. The light interacts with blood constituent moleculesand undergoes numerous scattering and absorption processes. This is astochastic process and the scattering of light is direction independent.Referring also to FIGS. 1A-1C and 2, part of the scattered light isreflected back into the probe and is collected via a second fiber core1620 that guides the collected light to a discrete photodiode 40. In thedescribed embodiment, the system-on-a-chip sends a time signal when thelaser emission wavelength is swept as a time function across thegain-bandwidth. During a scattering process with a blood-consistentmolecule, a resonant absorption process takes place if the laseremission frequency matches the rotational-vibrational frequency of thetarget molecule. Such a process results in the change of the time signalcollected by the discrete photodiode 40. Since the laser emissionwavelength is known precisely at all times, the collected time signalcan be reconstructed into wavelength space and molecular absorptionspectrum can be determined, and concentration level of the targetmolecule can be evaluated.

For a non-invasive sensor, the fiber-optic interface that includes aprobe does not connect to an intravascular catheter; rather, it is putinto contact with skin as shown in FIG. 17. It may also be connected toa fingernail of a patient. The structure of the fiber probe 1600 is verysimilar to the one used in the invasive case. Again, at least two fibercores are used. A first fiber core 1610 is used for coupling the lightfrom the system-on-a-chip. The light out-coupled from the fiber core1610 penetrates through outer skin layer 1730 such as epidermis andinteracts with blood constituent molecules, which are below theepidermis, in the dermis and subcutaneous tissue. The backscatteredlight is collected via the second fiber core 1620 which guides the lightto a discrete photodiode 40 at the sensor. The laser signal is convertedas a function of time and is then converted into wavelength space andmolecular absorption spectra are recovered, and concentration levelsidentified.

For infrared wavelengths close to and longer than 2 microns, typicalpenetration depth is a few millimeters. However, this is sufficient toreach the target blood molecules where the outer skin layer issufficiently thin, for instance, under the fingernails, earlobe, wrist,etc.

The described embodiments of the invention employ advanced integratedtechnology that does not use mechanically movable parts, and all drivesignals are based on electronics and photonics. The system-on-a-chip iscontrolled via a standard microcontroller, which controls the gain-chipdrive current, SoC heater currents based on the signal informationgathered from signal and wavelength monitoring sections, and comparesthe laser signal out-coupled from the sensor with the collected signal.This allows the elimination of systematic errors due to the system sothat the signal change due to interaction with the target molecule canbe identified.

Moreover, embodiments of the invention can be easily scaled to form amultiple molecule sensor. This may be achieved by forming an array ofoptical system-on-a-chip as in FIG. 18. Here the passive integratedoptical circuit array is realized within the same silicon based wafer.In case different target molecules with unique absorption features indifferent spectral regions that cannot be accessed within thegain-bandwidth of the single III-V gain-chip, the photonic integratedcircuit in silicon based chip may be designed in the form of lineararray, where each array cell is design for a specific wavelength ofinterest, e.g., array cell 1810 is designed around center wavelength λ₁,array cell 1820 is designed around a wavelength centered at λ₂, etc.Each individual laser cell out-couples to an individual output fiber viaan individual grating coupler. These fibers can be formed into a fiberbundle at the fiber probe end. The reflected signal, which carriesinformation about each target molecule, can be collected with a singlediscrete photodiode, given each laser cell wavelength sweep is emittedat different known time intervals, and detection is synchronized, asshown in FIG. 19.

For further optimization, the output of the SoC array can be organizedcouple to a single fiber core as shown in FIGS. 20, 21, and 22.Referring to FIG. 20, an array includes four array cells 1810, 1820,1830, 1840, and each individual cell output may be formed by individualgrating couplers, which are routed to an area of the chip where thegrating couplers can be covered with a single multimode fiber core 2000.In such an embodiment, the number of cells in the array from whichoutput may be collected with the single fiber core is limited by thefiber core cross-sectional area.

Another possibility is to use a wavelength switch and single gratingcoupler as shown in FIG. 21. Here, an array of four different cells1810, 1820, 1830, 1840 is illustrated, with the cells emitting at fourdifferent wavelength bands. Each cell is routed to a wavelength switch2100, which can be realized, for example, by a set of balancedMach-Zehnder interferometers 2110, 2120, 2130. A first MZI 2110 may beused to switch (using. e.g., heaters integrated on the arms of the MZI)between wavelengths λ₁ and λ₂ generated by the first and second SoCcells 1810 and 1820. In the same manner, a second balanced MZI 2120 maybe used to switch between wavelengths λ₃ and λ₄ generated by the thirdand fourth SoC cells 1830 and 1840. A third MZI 2130 switches betweenoutputs of the first and second MCIs 2110 and 2120, controlling whichcell of the four is out-coupled via a single grating coupler at anygiven moment of time. This concept can be scaled to an arbitrary numberof individual cells while still maintaining a single grating coupler forthe output of the array.

In the same manner, an SoC array can be realized using a single outputand a single output fiber 2000 in an end-fire coupling configuration asshown in FIG. 22.

To obtain calibrated concentration level data for a target metabolite,the concentration of other interfering molecular species contributing tothe spectral signature must be known. By far the most dominantoverlapping spectral signature is that of the water molecule, whichcontributes to over 95% of the total signal. In an embodiment of theinvention, a sensor array has at least two sensor cells, with at leastone of the cells being designed to have spectral wavelength tuningbandwidth in the vicinity of a water absorption peak. Referring to FIG.23, water absorption peaks occur at ˜1460 nm, ˜1900-2000 nm or ˜3000 nm.Thus, depending on the final sensor architecture, the cell's spectralwavelength tuning bandwidth can be near one of these peaks, where watermolecular absorption, which has a very well-known spectrum, is dominant.

The diffuse reflectance measurement using this sensor architecture maybe used to collect diffuse reflectance spectra R(λ), which in turn canbe converted to absorbance A(λ) by the relation:

${A(\lambda)} = {{\log_{10}\left( \frac{1}{R(\lambda)} \right)}.}$

The collected absorbance spectrum is composed of a sum from individualabsorbance spectral components of the contributing molecular species:

${A(\lambda)} = {{\sum\limits_{i}{A(\lambda)}_{i}} = {{A(\lambda)}_{H2O} + {A(\lambda)}_{lactate} + {A(\lambda)}_{Glucose} + \cdots}}$

Using the proposed sensor array architecture, a sensor may be designedsuch that each cell targets a different target molecule and individualabsorbance spectra of each target molecule are decoupled by using theinformation from the adjacent cells operating in different spectralregions where no multiple interference occurs. In this way, one or morethan one target component in the blood can be monitored.

Referring to FIGS. 24-25, spectral decomposition may be performed asfollows. FIG. 24 is a diffuse reflectance spectrum of a tris buffersaline (TBS) solution with lactates disposed in the solution, thespectrum having been obtained by FTIR measurement. FIG. 25 is aprocessed spectrum in which the TBS spectral component was subtracted,revealing the spectral component of a lactate molecule.

Accordingly, a very complex absorbance spectrum from a very complexscattering matrix—such as human tissue—can be decomposed into individualmolecular absorbance components and this absorbance can in turn beconverted to a calibrated concentration level by applying Lambert-Beerlaw:

A(λ)=ε₁(λ)c ₁+ε₂(λ)c ₂+ . . .

where ε_(i) is the calibrated molar attenuation coefficient and c_(i) isthe concentration.

Calibrated attenuation coefficients for each individual molecules arepredetermined and the values stored in the CPU for calibrated algorithmexecution to process the experimentally obtained diffuse reflectancespectrum—i.e., to decompose the spectrum into individual absorbancespectral components and calculate calibrated concentration levels.

In particular, in an embodiment, a sensor may include an array of cells,with at least one array cell targeted at a spectral region correspondingto at least one peak of water absorption, i.e., ˜1460 nm, ˜1900-2000 nm,or ˜3000 nm. Another cell in the array may be targeted at a spectralregion corresponding to at least one absorption peak of a bloodconstituent target molecule. The sensor may include a CPU that isprogrammed to determine a water concentration level and a waterabsorption spectrum based on the at least one peak of water absorptionmeasured with the at least one array cell. The CPU may also beprogrammed to remove a baseline and decompose a complex absorbancespectrum in spectral regions covered by array cells adjacent to the atleast one array cell to reveal underlying target molecule absorptionfeatures. Further, the CPU may be programmed to convert diffusereflectance spectra to absorbance. The absorbance may include acollected absorbance spectrum including a plurality of individualabsorbance spectral components decoupled by using information fromadjacent array cells operating in different spectral regions where nooverlap with other molecular absorption exists.

Since the depth and density of the capillary network varies withindifferent body parts, the sample volume also varies, and so does thereflectance signal. This challenge can be overcome with the describedapproach, in which a sensor array that includes a sensor cell targetingwater or other known molecule in the spectral region with nointerference is used. Thus, the water concentration level, which is alsoproportional to the sample volume, can be obtained independently of thesensor position within the human body, and the obtained data can furtherbe used to remove baseline and decompose the complex absorbance spectrumin the spectral regions covered by adjacent sensor cells.

The described algorithm in combination with the sensor architecturedescribed herein allows one to decompose an absorption spectrum ofarbitrary complexity into individual components and thus evaluate of theconcentration of each individual constituent. This may be facilitated byhaving prior knowledge of individual attenuation coefficients of eachindividual interfering species at a given wavelength. In circumstanceswhen the attenuation coefficients for some of the interfering speciesare not known, the ability to subtract any known or possible spectralcontributions greatly improves the accuracy of signal processingalgorithms such as multivariate partial least squares and principlecomponent regression method to obtain a calibrated concentration levelof a target molecule.

The described sensor architecture technology allows the decomposition ofa complex absorption spectra into individual components. When individualattenuation coefficients for every individual molecule are known, thistechnology provides a very straightforward way to get calibratedconcentration levels of each spectral component. However, the complexityof blood may create challenges. In such cases a typical approach mayinclude the use of multivariate PLS, which does not require all theunderlying components to be known. Even for PLS, the ability to subtractmajor interfering components such as water greatly improves the accuracyof the algorithm. Accordingly, in a preferred embodiment, the sensor hasattenuation coefficient data for several main molecules, and uses thisinformation together with the water signal to remove the baseline anduse multivariate PLS to get a calibrated concentration of the targetmolecule.

Referring to FIGS. 1C, 26, and 27, the described sensor may be used fornon-invasive concentration measurements, with the optical interface,e.g., fiber-optic interface 20, being used with additional beam shapingoptics to illuminate the blood in the dermis layer under the outer skinlayer or tissue via an optical link 2721. The reflected signal fromblood is collected via the optical link 2711 and guided to the reflectedlight photodiode 40. This situation is shown in greater detail in FIG.27, where the optical interface, e.g., fiber-optic interface 20 isdepicted as consisting of a focusing optics optical link 2721 and acollection optics optical link 2711.

In some embodiments the optical communication links 2721 and 2711 arefibers, e.g., optical fibers 12 and 31. In other embodiments, eachoptical communication link 2721 and 2711 may be an optical element,i.e., a lens or a set of lenses, a set of mirrors, and/or a parabolicmirror that form the optical communication link.

For example, the sensor array may have its output grating couplersrouted to a closely packed group in the same location within the opticalchip, as is shown in FIG. 20, except the multimode fiber core 2000 maybe replaced with a single focusing lens that focuses the output of eachgrating coupler on to the subject's blood under the outer layer of theskin non-invasively. The reflected light is collected by a separatelens, chosen so that its properties allow collection of light from thesame depth and location where the focused light is sent, enablingsensing. The collected reflected light is then focused to aphotosensitive aperture of the reflected light photodiode 40.

Referring to FIG. 28, during use of a system-on-a-chip sensor array,individual outputs of the photonic system-on-a-chip array cells 1810,1820, . . . 18XX , each providing a swept wavelength laser signal arounda different center wavelength, may be routed to one side of the photonicchip. Each individual output grating coupler 2810, 2820, . . . 2XXX isindividually focused with an individual focusing optical element, forexample, a lens 3010, 3020, . . . , 3XXX so that, in an optimal case,the beam spots of each the outputs overlap and form a single spot underthe subject's skin, ensuring that the interaction between the light fromthe sensor and the subject's blood is localized to a defined locationunder the skin. Typical light penetration depth is up to 1 mm under theskin, reaching the first vascularized layer—dermis layer. The diffuselyreflected light is then collected with a lens 4000, which is chosen sothat its numerical aperture and focusing depth allows collection of thereflected light from the location to which the light is focused. Thisreflected light carries information about light-blood interaction and iscollected by the lens 4000 and focused onto the photosensitive aperture2841 of the reflected light photodiode 40. The photosensitive aperture2841 is surrounded by a top electric contact 2842, which can act as acathode or anode—depending on the actual photodiode epitaxial structurelayer sequence—in combination with a second electrode 2844. The twoelectrodes are separated by an isolation gap 2843. For operation, thepolarity between the electrodes 2842 and 2844 is chosen so that thepn-junction is reverse biased.

The exact arrangement of the focusing optical lenses and the collectionoptical lenses is not critical as long as the focusing and collection isrealized from the same location—i.e., the same spot—within the subject.This is illustrated in FIG. 29, where the collection lens 4000 and thephotodiode 40 are realized in the center of the photonic chip array,whereas illumination of the sample is performed via the outputs routedto the perimeter of the photonic sensor chip.

Examples of Analysis

FIGS. 30a-30d shows absorption spectra of four molecules—glucose,lactate, bovine serum albumin and urea—recorded with a widely tunablelaser based sensor (curves a), and compared with spectra recorded with acommercial table-top FTIR spectrometer (curves b). In particular, thetested solutions were a) 30 mmol/l glucose b) 50 mmol/l lactate c) 50g/l bovine serum albumin (BSA) and d) 30 mmol/l urea. A clearcorrelation of the molecule-specific absorption spectrum measurement isvisible.

The CPU may be further programmed to correct and remove a baseline inspectral regions where absorption spectral features of more than onetarget molecule overlap. The baseline correction and removal is clearlyillustrated in FIGS. 31a and 31b . These illustrate spectroscopicmeasurements made using a commercial table-top FTIR spectrometer ofhuman blood samples, when the dual core fiber tip is directly dippedinto a blood droplet. FIG. 31a depicts a transmission spectrum of ablood droplet (curve d) and fitted water reflection spectrum (curve c).FIG. 31(b) depicts blood spectra with water being subtracted from theblood transmission measurement. The resulting curve is depicted as curvef which includes all blood constituent molecules except water(subtracted). As a guideline, curve e is a measured transmission curveof bovine serum albumin (BSA), which closely resembles human serumalbumin (HSA). Comparison of the two curves clearly indicates thespectral modulation from HSA on the blood measurement. The centralprocessing unit may be further programmed to determine a calibratedconcentration level using at least one of the individual absorbancespectral components, such as water or albumin. The calibratedconcentration level may be determined based on an individual absorbancevalue and a calibrated attenuation coefficient for each of a pluralityof individual molecules at a given wavelength. The central processingunit may be further programmed to determine a target moleculeconcentration independently of a particular sample volume.

In the case of non-invasive measurements, the sensor sends the lasersignal through skin, where light scatter and interacts with the tissuematrix. The laser signal reaches the upper capillary layer (˜0.2-0.3 mmbelow epidermis), where the light interacts with blood. Generally, thereare two types of reflectance: diffused and specular. Diffusedreflectance is the dominant reflectance when light interacts withtissue. A diffuse reflectance signal form a non-invasive measurement ofa human is shown in FIGS. 32a and 32b , where the shape of the complexreflectance spectrum measured non-invasively via skin of two differentpersons (FIG. 32a curves g and h) is compared with the invasive directmeasurement of a blood droplet when the fiber probe is directly immersedinto the blood (FIG. 32a curves i and j), clearly demonstrating thecapability of non-invasive measurement. Furthermore, in a similar manneras in FIG. 31, spectral decomposition can be applied to reveal thesignal of the underlying molecules in the blood, which can be seen inFIGS. 32b and 32c , where the blood signal modulation with human serumalbumin is shown in both cases measured by a table top FTIR spectrometer(FIG. 32b ) and non-invasively with a widely tunable laser sensor asdescribed herein. Modulation from the dominant HSA molecule around 2170nm is clearly visible.

The aforementioned specific chip arrangements are only a few examples ofthe many possible embodiments of the invention. The describedembodiments of the invention are intended to be merely exemplary andnumerous variations and modifications will be apparent to those skilledin the art. All such variations and modifications are intended to bewithin the scope of the present invention as defined in the appendedclaims.

The sensor system of the invention also contains the following featuresas set out in the clauses below:

-   -   1. A laser-based sensor system-on-a-chip for real-time        monitoring of a blood constituent concentration level in a        subject, the system-on-a-chip comprising:        -   a tunable hybrid III-V/IV laser sensor; and        -   a fiber-optic interface coupled to the laser sensor, the            interface comprising a probe,        -   wherein during use the laser sensor is remote from the            subject and the probe is in optical communication with the            subject.    -   2. A laser-based sensor system-on-a-chip of clause 1, wherein        the IV comprises a IV-based semiconductor substrate selected        from the group consisting of silicon, silicon-on-insulator,        silicon nitride on silicon-on-insulator, germanium-on-insulator,        and silicon nitride on silicon.    -   3. The laser-based sensor system-on-a-chip of clause 1, wherein        the tunable laser sensor comprises a III-V gain-chip and a        photonic integrated circuit disposed on a IV-based substrate,        the photonic integrated circuit (i) being configured to perform        wavelength filtering and tuning functions based on Vernier        effect and (ii) defining an external cavity for the III-V        gain-chip.    -   4. The laser-based sensor system-on-a-chip of clause 3, wherein        the photonic integrated circuit comprises a spot-size mode        converter, a phase control section, and a first resonator having        a first free-spectral range coupled to a second resonator having        a second free-spectral range.    -   5. The laser-based sensor system-on-a-chip of clause 4, wherein        the first and second resonators are selected from the group        consisting of micro ring resonators, sampled Bragg reflectors,        and distributed feedback reflectors.    -   6. The laser-based sensor system-on-a-chip of clause 4, wherein        the first free-spectral range is different from the second        free-spectral range.    -   7. The laser-based sensor system-on-a-chip of clause 4, wherein        the coupled first and second resonators, the III-V gain-chip,        spot-size mode converter, and phase control section cooperate to        enable Vernier effect-based tuning of the tunable laser sensor.    -   8. The laser-based sensor system-on-a-chip of clause 4, wherein        the tunable laser sensor is configured such that, in operation,        applying at least one of current or heat to at least one of the        coupled resonators to change an effective refractive index        thereof effects a change in a wavelength of a laser generated by        the gain-chip.    -   9. The laser-based sensor system-on-a-chip of clause 3, wherein        the III-V gain-chip is edge-coupled to the photonic integrated        circuit.    -   10. The laser-based sensor system-on-a-chip of clause 9, wherein        the III-V gain-chip is coupled to the photonic integrated        circuit by a grating coupler.    -   11. The laser-based sensor system-on-a-chip of clause 1, wherein        the laser sensor comprises at least one III-V photodiode coupled        to a photonic integrated circuit by at least one of flip-chip        bonding, gluing, transfer printing technology, or side coupling.    -   12. The laser-based sensor system-on-a-chip of clause 1, further        comprising a discrete III-V photodiode disposed remotely from        the tunable laser sensor, wherein, in use, a reflected signal        from the subject is collected by the discrete III-V photodiode.    -   13. The laser-based sensor system-on-a-chip of clause 12, where        the photonic integrated circuit comprises a signal and        wavelength monitoring section.    -   14. The laser-based sensor system-on-a-chip of clause 13,        wherein the signal and wavelength monitoring section        comprises (i) at least one of a set of Mach-Zehnder        interferometers or coupled ring resonators, and (ii) at least        one flip-chip III-V photodiode.    -   15. The laser-based sensor system-on-a-chip of clause 14, where        the laser sensor further comprises:        -   sensor control electronics; and        -   a signal processing microcontroller,        -   wherein the microcontroller is configured to (i) control the            laser drive electronics, (ii) tune currents, and (iii) use            information from the wavelength and signal monitor section            for signal processing of the data obtained from the discrete            III-V photodiode.    -   16. The laser-based sensor system-on-a-chip of clause 1, wherein        the laser sensor is configured to perform a wavelength sweep        across a tuning range as a function of time, and the laser        sensor comprises a photodiode configured to convert light        reflected from the subject into an electrical signal.    -   17. The laser-based sensor system-on-a-chip of clause 1, wherein        the fiber-optic interface is connected to an optical catheter        and is configured to (i) transmit a light signal from the sensor        to blood of the subject and (ii) transmit reflected light from        the blood of the subject to the sensor.    -   18. The laser-based sensor system-on-a-chip of clause 1, wherein        the fiber optic interface is in optical communication with beam        shaping optics configured to non-invasively illuminate a blood        sample of the subject through the subject's skin or outer        tissue.    -   19. A method of manufacturing a laser-based sensor system-on-a        chip for real-time monitoring of a blood constituent        concentration level in a subject, the method comprising the        steps of:        -   manufacturing a tunable hybrid III-V/IV laser sensor by        -   manufacturing a III-V semiconductor gain-chip,        -   fabricating a photonic integrated circuit on a group            IV-based semiconductor substrate by CMOS technology to            define a group IV semiconductor chip, and        -   hybridly integrating the III-V gain-chip and the group IV            semiconductor chip,        -   wherein the photonic integrated circuit is (i) configured to            perform wavelength filtering and tuning functions based on            Vernier effect and (ii) defines an external cavity for the            III-V gain-chip; and        -   coupling a fiber-optic interface to the laser sensor, the            interface comprising a probe,        -   wherein during use the laser sensor is remote from the            subject and the probe is in optical communication with the            subject.    -   20. The method of clause 19, wherein hybridly integrating the        III-V gain-chip and the group IV semiconductor chip comprises        edge-coupling the III-V gain-chip to the group IV semiconductor        chip, actively aligning the two chips, and gluing the two chips        together.    -   21. The method of clause 19, wherein hybridly integrating the        chips comprises flipping the III-V gain-chip p-side down and        bonding the gain-chip into a trench defined in the group IV        semiconductor chip for edge coupling to the photonic integrated        circuit.    -   22. The method of clause 19, wherein manufacturing the III-V        semiconductor gain-chip comprises epitaxially growing a laser        layer structure on a substrate by at least one of MBE or MOVPE        growth.    -   23. The method of clause 22, further comprising processing the        laser layer structure on the substrate into a gain-chip device        comprising predefined waveguide angles and contact pads.    -   24. The method of clause 23, further comprising cleaving the        laser layer structure on the substrate into bars.    -   25. The method of clause 24, further comprising forming an        anti-reflection coating on an output facet, wherein power        reflection is less than 0.1% at the output facet.    -   26. The method of clause 25, further comprising forming a        high-reflectivity coating on a back facet, wherein power        reflectivity is at least 90% or higher on the back facet.    -   27. The method of clause 26, further comprising cleaving each        bar into a plurality of individual III-V semiconductor        gain-chips.    -   28. The method of clause 27, further comprising designing a        photonic integrated circuit according to properties of the III-V        gain-chip, the photonic integrated circuit comprising at least        one of a spot size converter and a Vernier-filter.    -   29. A sensor comprising an array of cells, each cell comprising        a laser-based sensor system-on-a chip of clause 1, wherein each        array cell is targeted at a different spectral region and a        separate target molecule.    -   30. The sensor of clause 29, where a wavelength swept laser        signal of each array cell is emitted at a different time, and        signal collection is realized by synchronized detection with a        single photodiode.    -   31. The sensor of clause 29, wherein (i) the fiber-optic        interface comprises an out-coupling fiber having a core, (ii) an        output of the array is formed by a group of grating couplers        from the individual array cells routed to a same portion of the        system-on-a-chip and (iii) a total area defined by the group of        grating couplers is smaller than a cross-sectional area of the        out-coupling fiber core.    -   32. The sensor of clause 29, further comprising:        -   a single output section;        -   a wavelength switch configured to switch between outputs of            the array cells; and        -   a single photodiode,        -   wherein (ii) an output of the sensor array is formed by the            single output section and the wavelength switch, (ii)            switching between outputs of each individual cell results in            a single output of one array cell being out-coupled to the            target at a given time; and (iii) signal collection is            realized by synchronized detection with the single            photodiode.    -   33. The sensor of clause 29, wherein (i) at least one array cell        is targeted at a spectral region corresponding to at least one        peak of water absorption selected from the group consisting of        ˜1460 nm, ˜1900-2000 nm, and ˜3000 nm, and (ii) at least one        other array cell is targeted at a spectral region corresponding        to at least one absorption peak of a blood constituent target        molecule.    -   34. The sensor of clause 33, further comprising at least one        central processing unit programmed to determine a water        concentration level and a water absorption spectrum based on the        at least one peak of water absorption measured with the at least        one array cell.    -   35. The sensor of clause 34, wherein the central processing unit        is further programmed to remove a baseline and decompose a        complex absorbance spectrum in spectral regions covered by array        cells adjacent to the at least one array cell to reveal        underlying target molecule absorption features.    -   36. The sensor of clause 33, wherein the central processing unit        is further programmed to convert diffuse reflectance spectra to        absorbance.    -   37. The sensor of clause 36, wherein the absorbance comprises a        collected absorbance spectrum comprising a plurality of        individual absorbance spectral components decoupled by using        information from adjacent array cells operating in different        spectral regions where no overlap with other molecular        absorption exists.    -   38. The sensor of clause 37, wherein the central processing unit        is further programmed to correct and remove a baseline in        spectral regions where absorption spectral features of more than        one target molecule overlap.    -   39. The sensor of clause 38, wherein the central processing unit        is further programmed to determine a calibrated concentration        level using at least one of the individual absorbance spectral        components.    -   40. The sensor of clause 39, wherein the calibrated        concentration level is determined based on an individual        absorbance value and a calibrated attenuation coefficient for        each of a plurality of individual molecules at a given        wavelength.    -   41. The sensor of any of clauses 33-39, wherein the central        processing unit is further programmed to determine a target        molecule concentration independently of a particular sample        volume.    -   42. A laser-based sensor system-on-a-chip for real-time        monitoring of a blood constituent concentration level in a        subject, the system-on-a-chip comprising:        -   a tunable hybrid sensor; and        -   an optical interface coupled to the laser sensor, the            optical interface comprising beam-shaping optics,        -   wherein during use the laser sensor is remote from the            subject, and the optical interface is configured to            non-invasively illuminate a blood sample of the subject            through the subject's skin or outer tissue.    -   43. A sensor comprising an array of cells, each cell comprising        a laser-based sensor system-on-a chip of clause 42, wherein each        array cell is targeted at a different spectral region and a        separate target molecule.    -   44. The sensor array of clause 43, wherein an individual output        of each array cell is focused to illuminate a single area of the        subject, and each reflected signal is collected from the        illuminated area by the beam shaping optics.    -   45. The sensor array of clause 42, wherein the beam shaping        optics comprise at least one optical element.    -   46. The sensor array of clause 45, wherein the optical element        comprises at least one of a lens, a set of mirrors, and a        parabolic mirror.    -   47. A method of real-time monitoring of a blood constituent        level in a subject, comprising the steps of:        -   providing a system-on-a-chip comprising        -   a tunable hybrid III-V/IV laser sensor,        -   a fiber-optic interface coupled to the laser sensor, the            surface comprising a probe,        -   sensor control electronics for sensor control and signal            processing, and        -   a signal processing microcontroller, disposing the laser            sensor remote from the subject and the probe in optical            communication with the subject;        -   instructing the system-on-a chip to monitor the blood            constituent level in the subject by sending a swept laser            signal to the fiber optic interface;        -   guiding the signal with the fiber optic interface to the            blood of the subject;        -   after the signal interacts with the blood, collecting with            the fiber-optic interface a reflected signal from the blood;        -   guiding the reflected signal to a reflected light            photodiode, wherein the reflected signal is an optical            signal;        -   converting the reflected signal from an optical signal to an            electrical signal; and        -   processing the electrical signal with the microcontroller to            convert the electrical signal into a calibrated blood            constituent level.    -   48. The method of clause 47, wherein the probe is connected to        at least one of an intravenous optical catheter or an        intra-arterial optical catheter for invasive blood analyte        concentration level measurement.    -   49. The method of clause 47, wherein the optical interface is        attached to the subject for non-invasive blood analyte        concentration level measurement.    -   50. The method of clause 47, wherein the blood constituent is        selected from the group consisting of lactate, albumin, glucose,        ammonia, creatinine, and urea.

1. A laser-based sensor system-on-a-chip for real-time monitoring of ablood constituent concentration level in a subject, the system-on-a-chipcomprising: a tunable hybrid III-V/IV laser sensor; and a fiber-opticinterface coupled to the laser sensor, the interface comprising a probe,wherein during use the laser sensor is remote from the subject and theprobe is in optical communication with the subject.
 2. A laser-basedsensor system-on-a-chip of claim 1, wherein the IV comprises a IV-basedsemiconductor substrate selected from the group consisting of silicon,silicon-on-insulator, silicon nitride on silicon-on-insulator,germanium-on-insulator, and silicon nitride on silicon.
 3. Thelaser-based sensor system-on-a-chip of claim 1, wherein the tunablelaser sensor comprises a III-V gain-chip and a photonic integratedcircuit disposed on a IV-based substrate, the photonic integratedcircuit (i) being configured to perform wavelength filtering and tuningfunctions based on Vernier effect and (ii) defining an external cavityfor the III-V gain-chip. 4.-10. (canceled)
 11. The laser-based sensorsystem-on-a-chip of claim 1, wherein the laser sensor comprises at leastone III-V photodiode coupled to a photonic integrated circuit by atleast one of flip-chip bonding, gluing, transfer printing technology, orside coupling.
 12. The laser-based sensor system-on-a-chip of claim 1,further comprising a discrete III-V photodiode disposed remotely fromthe tunable laser sensor, wherein, in use, a reflected signal from thesubject is collected by the discrete III-V photodiode.
 13. Thelaser-based sensor system-on-a-chip of claim 12, where the photonicintegrated circuit comprises a signal and wavelength monitoring section.14. The laser-based sensor system-on-a-chip of claim 13, wherein thesignal and wavelength monitoring section comprises (i) at least one of aset of Mach-Zehnder interferometers or coupled ring resonators, and (ii)at least one flip-chip III-V photodiode.
 15. The laser-based sensorsystem-on-a-chip of claim 14, where the laser sensor further comprises:sensor control electronics; and a signal processing microcontroller,wherein the microcontroller is configured to (i) control the laser driveelectronics, (ii) tune currents, and (iii) use information from thewavelength and signal monitor section for signal processing of the dataobtained from the discrete III-V photodiode.
 16. The laser-based sensorsystem-on-a-chip of claim 1, wherein the laser sensor is configured toperform a wavelength sweep across a tuning range as a function of time,and the laser sensor comprises a photodiode configured to convert lightreflected from the subject into an electrical signal.
 17. Thelaser-based sensor system-on-a-chip of claim 1, wherein the fiber-opticinterface is connected to an optical catheter and is configured to (i)transmit a light signal from the sensor to blood of the subject and (ii)transmit reflected light from the blood of the subject to the sensor.18. The laser-based sensor system-on-a-chip of claim 1, wherein thefiber optic interface is in optical communication with beam shapingoptics configured to non-invasively illuminate a blood sample of thesubject through the subject's skin or outer tissue.
 19. A method ofmanufacturing a laser-based sensor system-on-a chip for real-timemonitoring of a blood constituent concentration level in a subject, themethod comprising the steps of: manufacturing a tunable hybrid III-V/IVlaser sensor by manufacturing a III-V semiconductor gain-chip,fabricating a photonic integrated circuit on a group IV-basedsemiconductor substrate by CMOS technology to define a group IVsemiconductor chip, and hybridly integrating the III-V gain-chip and thegroup IV semiconductor chip, wherein the photonic integrated circuit is(i) configured to perform wavelength filtering and tuning functionsbased on Vernier effect and (ii) defines an external cavity for theIII-V gain-chip; and coupling a fiber-optic interface to the lasersensor, the interface comprising a probe, wherein during use the lasersensor is remote from the subject and the probe is in opticalcommunication with the subject.
 20. The method of claim 19, whereinhybridly integrating the III-V gain-chip and the group IV semiconductorchip comprises edge-coupling the III-V gain-chip to the group IVsemiconductor chip, actively aligning the two chips, and gluing the twochips together.
 21. The method of claim 19, wherein hybridly integratingthe chips comprises flipping the III-V gain-chip p-side down and bondingthe gain-chip into a trench defined in the group IV semiconductor chipfor edge coupling to the photonic integrated circuit.
 22. The method ofclaim 19, wherein manufacturing the III-V semiconductor gain-chipcomprises epitaxially growing a laser layer structure on a substrate byat least one of MBE or MOVPE growth. 23.-28. (canceled)
 29. A sensorcomprising an array of cells, each cell comprising a laser-based sensorsystem-on-a chip of claim 1, wherein each array cell is targeted at adifferent spectral region and a separate target molecule.
 30. The sensorof claim 29, where a wavelength swept laser signal of each array cell isemitted at a different time, and signal collection is realized bysynchronized detection with a single photodiode.
 31. The sensor of claim29, wherein (i) the fiber-optic interface comprises an out-couplingfiber having a core, (ii) an output of the array is formed by a group ofgrating couplers from the individual array cells routed to a sameportion of the system-on-a-chip and (iii) a total area defined by thegroup of grating couplers is smaller than a cross-sectional area of theout-coupling fiber core.
 32. The sensor of claim 29, further comprising:a single output section; a wavelength switch configured to switchbetween outputs of the array cells; and a single photodiode, wherein(ii) an output of the sensor array is formed by the single outputsection and the wavelength switch, (ii) switching between outputs ofeach individual cell results in a single output of one array cell beingout-coupled to the target at a given time; and (iii) signal collectionis realized by synchronized detection with the single photodiode. 33.The sensor of claim 29, wherein (i) at least one array cell is targetedat a spectral region corresponding to at least one peak of waterabsorption selected from the group consisting of ˜1460 nm, ˜1900-2000nm, and ˜3000 nm, and (ii) at least one other array cell is targeted ata spectral region corresponding to at least one absorption peak of ablood constituent target molecule. 34.-41. (canceled)
 42. A laser-basedsensor system-on-a-chip for real-time monitoring of a blood constituentconcentration level in a subject, the system-on-a-chip comprising: atunable hybrid III-V/IV sensor; and an optical interface coupled to thelaser sensor, the optical interface comprising beam-shaping optics,wherein during use the laser sensor is remote from the subject, and theoptical interface is configured to non-invasively illuminate a bloodsample of the subject through the subject's skin or outer tissue.
 43. Asensor comprising an array of cells, each cell comprising a laser-basedsensor system-on-a chip of claim 42, wherein each array cell is targetedat a different spectral region and a separate target molecule.
 44. Thesensor array of claim 43, wherein an individual output of each arraycell is focused to illuminate a single area of the subject, and eachreflected signal is collected from the illuminated area by the beamshaping optics.
 45. The sensor array of claim 42, wherein the beamshaping optics comprise at least one optical element.
 46. (canceled) 47.A method of real-time monitoring of a blood constituent level in asubject, comprising the steps of: providing a system-on-a-chipcomprising a tunable hybrid III-V/IV laser sensor, a fiber-opticinterface coupled to the laser sensor, the surface comprising a probe,sensor control electronics for sensor control and signal processing, anda signal processing microcontroller, disposing the laser sensor remotefrom the subject and the probe in optical communication with thesubject; instructing the system-on-a chip to monitor the bloodconstituent level in the subject by sending a swept laser signal to thefiber optic interface; guiding the signal with the fiber optic interfaceto the blood of the subject; after the signal interacts with the blood,collecting with the fiber-optic interface a reflected signal from theblood; guiding the reflected signal to a reflected light photodiode,wherein the reflected signal is an optical signal; converting thereflected signal from an optical signal to an electrical signal; andprocessing the electrical signal with the microcontroller to convert theelectrical signal into a calibrated blood constituent level.
 48. Themethod of claim 47, wherein the probe is connected to at least one of anintravenous optical catheter or an intra-arterial optical catheter forinvasive blood analyte concentration level measurement.
 49. The methodof claim 47, wherein the optical interface is attached to the subjectfor non-invasive blood analyte concentration level measurement.
 50. Themethod of claim 47, wherein the blood constituent is selected from thegroup consisting of lactate, albumin, glucose, ammonia, creatinine, andurea.